18-oxygenated steroids and process for their manufacture



United States Patent 0 3,234,213 lit-OXYGENATED STEROEDS AN PRGCESS FGRTElEl'R MANUFACTURE ()skar Jeger, Zurich, Basilio Arigoni,Zollilrerberg, Georg Anner and Charles Meystre, Basel, and AlbertWettstein, Riehen, witzerland, assignors to Cilia Corporation, acorporation of Delaware No Drawing. Filed Feb. 9, 1960, Ser. No. 7,543Claims priority, application Switzerland, Apr. 23, 1959, 72,443/59; Dec.22, 1959, 82,231/59 15 Claims. (Cl. 260-43955) The present inventionrelates to a process for the manufacture of ill-oxygenated steroids fromIii-unsubstituted steroids.

The lS-oxygenated steroids, particularly lit-oxygenated pregnanes, areof great interest on account of their interesting physiological effects.To this class of compounds there belongs, inter alia, aldosterone whichis of consider- 3,2342% laiented Feb. 8, 1966 process it is now possibleto obtain 18-oxygenated steroids, especially Ill-oxygenated prenanes,that is to say also aldosterone and its derivatives and relatedcompounds, in a simple manner by a direct selective substitution of theangular, non-activated methyl group at car bon atom 13 in the intactsteroid skeleton. Thus, 18- oxygenated steroids can now be prepared inany quantity from readily accessible vegetable and animal steroids.

The new process comprises three main parts:

(1) The formation of an 18:20-ether starting from an l8-unsubstitutedZO-hydroxy-pregnane,

(2) The splitting or oxidative conversion of the 18:20- ether intol8-hydroxy or IS-acid derivatives,

(3) The further oxidation of the resulting polyoxygenated lS-hydroxycompounds.

One method is shown in the following diagram of partial formulae with anll-oxygenated compound as example:

H O C Ha 0 H3 0 H Ac 0 i he =acyl radical Part 1 lead tetraacetate 02oxidatioy l &c OH- L B F:

AcCI) (3H3 (3A0 13H: A00 (5H5 CH2 OHOAc CH3 ('lH %Hz CH Ha] AcO-- AcO-AcO-- Part 2 base l hydrolysis l Hydrolysis O H C H: ?H (5H2 Hz O HO H 0Hz C H HO HO i I Part 3 l oxidation 1 oxidation 0 gH C HO O H ableimportance owing to its specific effect on electrolyte-metabolism. Thelatter compound, however, is present in the suprarenal glands only in anextremely small quantity. Larger amounts could hitherto only be preparedby total synthesis from simple chemical basic substances involving manysteps. According to the present and, if desired, in the resultingoxidation products, if desired after introducing a 4:5-double bondand/or ketalizing the oxo groups in 3-, 18- and/or 20-position, reducingany li-oxo group present to 11-,8-hydroxy group and oxidizing aresulting 13:11-lactone of an 115:20-dihydroxy-pregnane-lS-acid to forma 20-oxo compound.

For the oxidation according to the present process various oxidizingagents which can bring about dehydrogenation of alcohols to formcarbonyl compounds are suitable, especially compounds of hexavalentchromium, such as sodium dichromate or especially chromium trioxide inglacial acetic acid, in acetone with the addition of sulfuric acid, oralso in pyridine. Oxidation can also be carried out with anN-halogencarboxylic acid amide or imide, such as bromosuccinimide,bromacetamide and the like. Depending on the conditions used in theoxidation of 18:20-dihydroxypregnanes difierent products are obtainedwith chromium trioxide. With energetic conditions, for example inglacial acetic acid or in acetone with the addition of sulfuric acid,the 18-hydroxyl group is surprisingly quickly attached, so that as mainproduct lactones of ZO-hydroxy-pregnane-lS-acids are formed. In addition18:20-dioxo compounds (20-keto-18-als) and 18-hydroxy-20-ketones canalso be formed in smaller quantities which are obtained in the form oftheir cycloherniketals. The two last compounds are formed primarily inthe case of mild oxidation With chromium trioxide in pyridine. Freehydroxyl groups in 3- and/or ll-position are dehydrogenated to ketonesduring oxidation according to the present process.

If desired, subsequent to the oxidation, a double bond can be introducedin ring A by bromination and dehydrobromination in a manner known per seespecially in those compounds which have no oxo group in the 20-position(e.g. in l-actones of 20-hydroxy-pregnane-18-acids).

Free oxo groups in 3-, 18- and/or 20-position can also be protected byketalization with ethylene glycol, propylene glycol et. in the presenceof an acidic catalyst. In these protected compounds, if desired, anyll-keto group present can be reduced with a complex metal hydride, forexample sodium boron hydride, lithium boron hydride or lithium aluminumhydride. In the case of lactones of 11-oxo-ZO-hydroxy-pregnane-18-acidsthe use of sodium boron hydride, e.g. in alkaline solution, isespecially advantageous; under these conditions translactionization ofthe 18:20-lactones to 18:1l-lactones occurs simultaneously with thereduction of the ll-oxo group. By subsequent oxidation of the resultingfree ZO-hydroxyl group to the 20-ox0 group, for example with chromiumtrioxide and pyridine, the 18:11-lactone of pregnane-20- ketone istherefore readily obtained; the conversion of this compound intoaldosterone and its derivatives is already known.

As starting materials for the present process are especially suitable18:20-dihydroxy compounds of the 50cand SIR-pregnane series which maycontain further substituents in the ring system, particularly free orfunctionally converted hydroxyl groups and oxo groups especially in the3- and ll-position. The compounds may also contain double bonds, forexample starting from carbon atom 5 and/or in 9:11-position. Byfunctionally converted hydroxyl or oxo groups are to be understoodesterified or etherified hydroxyl groups and ketalized oxo groupsrespectively The starting materials are obtained by the process ofpatent application No. 7,525, filed February 9, 1960, and No. 7,542,filed February 9, 1960, for example by treating the corresponding18-unsubstituted ZO-hydroxy compounds with lead tetra-acetate, thensplitting the resulting 18:20-ether with acetic anhydride in thepresence of boron trifluoride, and hydrolysis.

The present invention also concerns the l8r20-lactones of20-hydroxy-steroid-lB-acids, especially the 18:20- lactoncs of20-hydroxy-pregnane-l8-acids, for example the 1S :20-lactone of 3l1-dioxo-ZO-hydroxy-pregnane-18- acid, saturated or unsaturated in the4:5-position, and the 18:20-lactone of3/3:20-dihydroxy-5a-pregnane-lS-acid and its 3-esters and saturated3:18:20-trioxo-pregnanes, such as 3: l8:20-trioxo-5oc-pregnane, 3:11:18:20-tetraoxo-Sfl-pregnane, 3 18 20-trioxo-1 IB-acetoxy-S a-pregnaneand A -3:11218:20-tetra-oxo-pregnene and the derivatives, for exampleketals and esters, of these compounds.

The invention also comprises saturated, 2l-unsubstituted ll-oxygenated18-hydroxy-20-oxo-pregnanes present in the form of 18:20-hemiketals,such as 3:11:20- trioxol 8-hydroxy-5/3-pregnane, 3 :20-dioxo-l1u:l8-dihydroxy 5B pregnane and 3:11:20-trioxo-18-hydroxy-5otpregnane.

Resulting compounds containing no oxygen function in ll-position can beoxidized in known manner, advantageously after introduction of the A-3-keto grouping, with the aid of micro-organisms to form 11-oxygenatedcompounds.

The following examples illustrate the invention:

Example 1 100 mg. of 3B:18:20g-trihydroxy-5a-pregnane are dissolved in'5cc. of pyridine and the solution added dropwise to a suspension of 100mg. of chromium trioxide in 5 cc. of pyridine at room temperature. After90 minutes the solution is filtered from the precipitate, 10 cc. ofmethanol are added to destroy any excess oxidizing agent and thereaction mass worked up. 99 mg. of a crystalline crude product saturatedagainst tetranitromethane are obtained which, after being recrystallizedthree times from a mixture of methanol and water, melt at 144-145 C.Optical rotation: [a] :+68 (in chloroform). Infrared absorptionspectrum: bands at 3.68 (IS-aldehyde), broad bands at 5.81-5.89u(3:18:20-carbonyls), The product is 3: 18:20-trioxo-5 tat-pregnane.

By treating :18:20 trihydroxy 115 acetoxy-5apregnane with chromiumtrioxide in pyridine in the above described manner,3:18:20-trioxo-115-acetoxy-5apregnane is formed. In a 3:18:20-trisethylenedioxy-11/3- acetoxy-Sa-pregnane obtained byketalization the ester grouping in the l1-position can advantageously behydrolyzed by treatment with lithium aluminum hydride intetrahydrofuran. The reaction mixture is then adjusted .to pH 4-4.5 withdilute aqueous acid and kept for a few hours at room temperature,whereby the ketal groupings at carbon atoms 3, l8 and 20 are alsohydrolyzed. As end product of this sequence of reactions the l1 18-semiacetal of 3: 18:20-trioxo-1Ifi-hydrQXy-Sapregnane is obtained whichis oxidized with the acid of cromium tri oxide in glacial acetic acid toform the 11 18-lactone of 3 20-diketo-1 1 fi-hydroxy-S a-pregnanel8-acid.

In an analogous manner, on oxidizing 1 gram of3a:11a:18:20-tetrahydroxy-Sfi-pregnane with 800 mg. of

' chromium'trioxide in cc. of pyridine, there is obtained crystalline3:11:18:20-tetraoxo-5fl-pregnane after purification by chromatography.The latter product can be converted into 3:18:20 trisethylenedioxy-ll-keto-SB- pregnane by boiling for 4 hours in a benzenesolution with ethylene glycol in the presence of a trace ofparatoluene-sulfonic acid. The reaction product is then converted into3:18:20 trisethylenedioxy-llfi-hydroxy-Sfipregnane in high yield byreduction with lithium aluminum hydride in absolute tetrahydrofuran. Theketal groupings of 3:18:ZO-tris-ethylenedioxy-l1fl-hydroxy-5B-pregnaneare hydrolyzed by being treated with aqueous acetic acid of 50%strength for one hour on a water bath.

mg. ofthe resulting 11 18-semi-acetal of 3:18:20 trike'to-llflghydroxy-Sfi-pregnane are then dissolved in 10 cc. of pyridine and 50mg. of chromium trioxide added to the solution. After allowing the wholeto stand for 2 hours at room temperature, the excess oxidizing agent isdestroyed by the addition of a little methanol and the reaction mixtureworked up in known manner, 92 mg. of

a crystalline crude product being obtained which, for the purpose ofpurification, is dissolved in 10 cc. of a mixture of petroleum ether andbenzene (1:1) and chromatograp-hed through a column of 6 grams ofaluminum oxide of activity I-II. 67 mg. of substance are eluted from thecolumn with a mixture of petroleum ether and benzene (1:4) and withbenzene and then recrystallized from acetone or chloroform-methanol. Theproduct is the 1 1 18-lactone of 3 ZO-diketo-l 1 3-hydroxy-5 B-pregnane-Ill-acid which in the infra-red absorption spectrum exhibits bands at564 (ll- 18-lactone) and at 5.85;]. (chloroform) By brominating the 1118-lactone of 3:20-diketo-11,6- hydroxy-SB-pregnane-18-acid with one molof bromine the corresponding 4-bromo derivative is obtained which, onbeing treated with lithium chloride in dimethylformamide, yields the 1118-lactone of M-3220-diketo-llfihydroxy-pregnene-lS-acid which isidentical in all its properties with the compound obtained bydegradation of aldosterone.

Example 2 A solution of 1 gram of A-3-keto-l1,9:18:20-trihydroxy-pregnene in 75 cc. of pyridine is treatedwith 1 gram of chromium trioxide for 3 hours at room temperature.Working up and chromatographic purification on silica gel yield 690 mg.of A -3:11:18:20-tetraoxo-pregnene which exhibits in the infra-redspectrum (in chloroform) at 3.68 5.87 5.94 i/6.l9,u the characteristicbands of its 4 carbonyl groups.

Example 3 A solution of 4.9 grams of chromium trioxide in 10 cc. ofwater and 140 cc. of glacial acetic acid is added at such a speed to asolution of 4.59 grams of 3&11106118120atetrahydroxy-Sfi-pregnane in 300cc. of glacial acetic acid while cooling with ice water and stirringthat the internal temperature does not exceed 16 C. The reaction mixtureis stirred for 17 /2 hours at room temperature, a solution of 3 grams ofsodium sulfite in 50 cc. of water is added and the mixture evaporated toa volume of 100 cc. at a water-jet vacuum at a bath temperature of 40 C.The solution is diluted with 400 cc. of sodium chloride solution of 6%strength, extracted four times with 300 cc. of methylene chloride andthe organic solution washed twice with 400 cc. of sodium chloridesolution of 6% strength. The methylene chloride solutions are dried andevaporated at a Weter-jet vacuum and the residue dissolved in 50 cc. ofbenzene and chromatographed on 25 grams of silica gel (containing 15 ofwater). The fractions eluted with a mixture of benzene and ethyl acetate(9:1) are recrystallized from a mixture of methylene chloride and etherto yield 1.45 grams of the 18 20- lactone of3:1I-diketo-ZOa-hydroxy-SB-pregnane-1S-acid melting at 213.5214 C.Further recrystallization raises the melting point to 2l4.5215 C.Optical rotation: [a] =-i1 (in chloroform). Infrared spectrum (solvent:methylene chloride): -65/L ('ylactone) and 5.82; (3-ketone+ 1 l-ketone)When a mixture of 0.267 gram of chromium trioxide and 0.23 cc. ofsulfuric acid made up to 1 cc. with Water is added to a solution of 102mg. of 3a:11u:18:20 x-tetra hydroxy-SB-pregnane in 12 cc. of acetone inthe course of a minute with ice cooling and stirring, there are obtainedafter minutes stirring at 0 C., working up and chroma tography on silicagel, 15 mg. of the above described lactone.

A solution of 1.45 grams of the 18- 20-lactone of 3:11-diketo-ZOa-hydroX -Sfiregnane-18-acid in 45 cc. of glacial acetic acidis treated with 1.7 cc. of a 0.1 N-solution of hydrobromide in glacialacetic acid and then in the course of ten minutes with stirring with 12cc. of a 0.735 N-solution of bromine in glacial acetic acid containing386 mg. of sodium acetate. The reaction solution is diluted with 250 cc.of water, extracted three times with methylene cholride and the organicsolutions washed once with 300 cc. of saturated sodium bicarbonatesolution and once with cc. of water. The organic solutions are dried andevaporated at a water-jet vacuum at a bath temperature of 35 C., theresidue is added with 10 cc. of dimethylformamide to a mixture of 1.5grams of dry lithium chloride, 1.5 grams of lithium carbonate and 30 cc.of dimethylformarnide which has been previously heated in a current ofnitrogen at 100 C. with stirring for 45 minutes and then cooled. Thereaction mixture is heated for two hours in a current of nitrogen at 100C. with stirring, allowed to stand overnight at room temperature andpoured on to 150 cc. of water and 3 cc. of glacial acetic acid andextracted three times with cc. of methylene chloride. The methylenechloride extracts are washed twice With 150 cc. of water, dried andevaporated at a Water-jet vacuum. To remove dimethylfornr amide thereaction solution is dissolved in xylene, evaporated at a water-jetvacuum, and this operation is repeated once with xylene and once withbenzene. The residue is chromatographed on 75 grams of silica gel(containing 15% of water). The crystalline fractions obtained withmixtures of benzene and ethyl acetate (9:11) and (4:1) arerecrystallized from a mixture of methylene chloride and ether to yield630 mg. of the 18- ZO-lactone of A3:11-diketo-20a-hydroxy-pregnene-1S-acid which, after sublimation at 200C. in a high vacuum and recrystallization, melts at 257 C. 6 ,,=14500;optical rotation [a] =+l4U (in chloroform). Infra-red spectrum (solventmethylene chloride): 5.65s ('y-lactone); 5.80 2 (l1- ketone) and5.96,u+6.16,e (A -3-ketone).

605 mg. of the 18- 20-lactone of A-3Z11-diketO-20ahydroxy-pregnene-l3-acid are treated with a solution of36 mg. of para-toluene-sultonic acid in 60cc. of ethylene glycol,whereupon 15 cc. of the solvent are distilled ed at a water-jet vacuumin the course of 30 minutes with stirring. treated with cc. of water and5 cc. of saturated sodium bicarbonate solution and extracted three timeswith methylene chloride. The organic solutions are Washed twice withwater, dried and evaporated at a water-jet vacuum. The residue ischromatographed on 25 grams of silica gel (containing 15% of water). Thefractions eluted with a mixture of benzene and ethyl acetate (9:1) arerecrystallized from a mixture of methylene chloride and ether to yield390 mg. of the 189 ZO-lactone of A -3 ethylenedioxy 11lreto-ZOa-hydrOXy-pregnene 18 acid which, after furtherrecrystallization, melts at 274275.5 C. Optical rotation: [u] =23.5 (inchloroform). Infra-red spectrum (solvent: methylene chloride): 566('y-lactone); 5.82 (ll-ketone) and 9.08 (ketal).

200 mg. of sodium boron hydride are added to a suspension of 130 mg. ofthe 18 20-lactone of A -3-ethylenedioxy-l1-keto-20ot-hydroxy-pregnene-l8-acid in 9 cc. of alcohol and 1 cc, of N-sodium hydroxide solution.After stirring for 4 /2 hours at room temperature, 10 cc. oftetrahydrofuran are added, the substance dissolving. 22 hours later afurther 100 mg. of sodium boron hydride is added and the whole is thenstirred for 28 hours at 40 C. The reaction solution is then poured on towater and 1 cc. of glacial acetic acid, extracted four times withmethylene chloride, Washed once with Water, dried and evaporated at awater-jet vacuum. The crystalline residue consisting of the 18-11-lactone of A 3-ethylenedioxy- 11,8:20e-dihydroxy-pregnene-1S-acid isadded with 5 cc. of pyridine to a mixture of 100 mg. of chromiumtrioxide and 5 cc. of pyridine with ice-cooling and stirring. Thereaction mixture is stirred for 16 hours at room temperature, dilutedwith water and extracted three times with benzene and filtered throughCelite to separate ofi any undissolved constituents. The organicsolutions are Washed twice more with water, dried and evaporated at awater-jet vacuum. The reaction mass is dissolved in The violet coloredreaction solution is then xylene, evaporated again at a water-jetvacuum, and this operation is repeated once with benzene. The resultingcrystalline residue is chromatographed on 8.5 grams of silica gel(containing 15% of water). The crystalline fractions eluted with amixture of benzene and ethyl acetate (9: 1) are recrystallized from amixture of methylene chloride and ether to yield 43 mg. of the 1811-lactone of A -3-ethylenedioxy-11p-hydroxy-ZO-keto-pregnene 18- acidmelting at 239.5240.5 C. Optical rotation: [02113 +1 (in chloroform).Its infra-red spectrum (solvent: methylene chloride) is identical withthat of the authentic 18 11-lactone of d,l-A-3-ethylenedioxy-11;3-hydroxy-20- keto-pregnene- 1 8-acid.

The conversion of this product into aldosterone is carried out in knownmanner by condensation of the oxalic ester to the 21-oxaloester meltingat 160175 C., iodisation, treatment with potassium acetate to form the21-acetate melting at 237.5239.5 C. (optical rotation [a];;,: ---33 inchloroform) and hydrolysis to form the 18- 11- lactone of A-3:ZO-diketo-l118:21-dihydroxy-pregnene-18- acid melting at 214-217 C.(optical rotation [a] +173 in chloroform). The above compound issubjected in known manner to ketalization, reduction with lithiumaluminum hydride, acetylation and ketal-splitting to form the21-monoacetate of aldosterone.

Example 4 250 mg. of 3a:11a:18:ZOa-tetrahydroxy-SB-pregnane are added toa mixture or" 500 mg. of chromium trioxide and cc. of pyridine withstirring and ice cooling and the mixture is then stirred for 15 hours atroom temperature. It is then diluted with water and extracted threetimes with benzene and then filtered through Celite to separate off anyundissolved constituents. The organic solutions are washed twice withwater, twice with 2 N- sodium carbonate solution and twice with water.The organic solutions are dried and evaporated in a waterjet vacuum andthe residue dissolved in xylene, and this operation repeated once withbenzene. Chromatography is carried out on 12.5 grams of silica gel(containing 15% of water) and the following compounds elutedsuccessively with mixtures of benzene and ethyl acetate: (a) 8.5 mg. ofthe 18- 20-lactone of 3: 11-diketo-20ot-hydroxy- 5fl-pregnane-18-aciddescribed in Example 3. The infrared spectra are identical. (b) mg. ofthe 18 20- cyclohemiketal of 3:11:20-triketo-18-hydroxy-5B-pregnanemelting at 186.5-194 C. Further recrystallization from a mixture ofmethylene chloride, ether and petroleum ether raises the melting pointto 1925-1955 C. Infra-red spectrum (solvent: methylene chloride):2.75,u+2.91p. (hydroxyl) and 5.82 (3-ketone+ll-ketone). (c) 10 mg. of3:11:Zil-triketo-18-oxo-5B-pregnane melting at 248.5-252.5 C. Infra-redspectrum (solvent: methylene chloride): 3.61 (aldehyde) and 5.82, withinflexion at 5.78;/. (3, 11 and 20-ketone+aldehyde).

Example 5 A solution of mg. of 3111-diketo-18:20a-dihydroxy-5,8-pregnane in 10 cc. of acetone is treated for 30 minutes at 0 C. with1 cc. of Kiliani solution. After adding a little methanol, the solutionis worked up in the ordinary manner, 57 mg. of a neutral portion beingobtained which crystallizes on being sprinkled with methanol. Thecrystals are filtered in a benzene solution through a small column ofaluminum oxide of activity II, and the resulting (18 20)-lactone of3:11-diketo-20a-hydroxy-5B- pregnane-lS-acid has a constant meltingpoint of 211- 212 C. after being recrystallized three times from amixture of acetone and heptane. Optical rotation: [a] 0.5. Infra-redspectrum: bands at 5.65 and 5.81 in Nujol.

Example 6 120 mg. of chromium trioxide dissolved in 5 drops of Water and10 cc. of glacial acetic acid are added to 150 mg. of 38:18:2Oa-trihydroxy-Sa-pregnane in 20 cc. of glacial acetic acid and thewhole allowed to stand overnight at room temperature. The mixture istreated with a few drops of methanol and worked up with ether in theusual way. The crystalline crude product (168 mg.) is purified bychromatography on neutral aluminum oxide (activity II). With a mixtureof petroleum ether and benzene (1:1) mg. of20ct-hydroxy-3-keto-5a-pregnane- 18-acid-lactone are eluted from thecolumn which has a constant melting point of 174-175 C. after beingcrystallized three times from a mixture of methanol and water. Opticalrotation [a] +17; infra-red spectrum; bands at 5.68;. and 5.84,u. inchloroform.

500 mg. of sodium boron hydride are added to 130 mg. of the abovelactone dissolved in 30 cc. of absolutedioxane and the whole boiledunder reflux for 2 hours. The mixture is poured on to dilute sulfuricacid and worked up with ether in the ordinary manner. The resultingcrude product (120 mg.) is purified by chromatography on neutralaluminum oxide (activity 11). An oil mg.) which cannot be made tocrystallize is eluted with benzene. The crude hydroxy-lactone isacetylated overnight at room temperature with 10 cc. of pyridine-aceticanhydride (1:1). Usual working up yields a crystalline product mg.)which is chromatographed on neutral aluminum oxide (activity II). With amixture of petroleum and benzene (9:1) 75 mg. of3fi-acetoxy-20ot-hydroxy-5apreg-nane-lS-acid-lactone are eluted which,after being crystallized three times from a mixture of methanol andwater, has a constant melting point of 196-497 C. Optical rotation:[a],;: 14; infra-red spectrum; bands at 5.68;! 5.80 and 8.00 "inchloroform.

To 35 mg. of this compound dissolved in 15 cc. of tetrahydrofuran about200 mg. of lithium aluminum hydride are added and the mixture boiledunder reflux for one hour. The excess lithium aluminum hydride isdestroyed by adding water dropwise to the ice-cold mixture, the reactionproduct poured on to dilute sulfuric acid and worked up with ether inthe usual manner. After being recrystallized twice from methanol-waterthe crystalline 3Bz18: ZOu-trihydrOXy-Saregnane has a constant meltingpoint of l24-l25 C. [a] +36.

What is claimed is:

1. A member selected from the group consisting of a compound having theformula in which R R and R each represents a member selected from thegroup consisting of =0 and OHR;

and R 21 member selected from the group consisting of and H 0 wherein Ris a member selected from the group consisting of and and theircorresponding Sa-pregnane derivatives.

3. An 18:20 hemiketal of the compound claimed in claim 2.

. 3 18:20-trioxo-5 wpregnane.

. 3 :11 18 :20tetraoxo-5,B-pregnane.

. 3 18 :ZO-trioxo-l 1/8-acetoxy-5a-pregnane.

. A -3 1 1 t 18 ZO-tetraoxo-pregnene.

. 3 1 l :ZO-trioxo-18-hydroxy-5B-pregnane.

Process wherein an 18:20-1actone of A-3-ethylenedioxy-l1-oxo-20-hydroxy-pregnene-18-acid is reduced inalkaline solution with sodium boron hydride and the resulting18:11-lactone of A -3-ethylene-dioxy-1lfizZO-dihydroxy-pregnene-18-acidoxidized with chromium trioxide in pyridine.

10. Process for the manufacture of a member selected from the groupconsisting of a ZO-hydroxy-steroid 18- aldehyde and a ZO-hydroxy-lS-acidof the pregnane series and their cyclohemiacetals and lactones, whereina 10 member selected from the group consisting of an 18:20-dihydroxy-pregnane, an 18:20 dihydroxy-allopregnane andA-4:5-derivatives thereof, is treated with a compound of hexavalentchromium.

11. Process as claimed in claim 10, wherein in a steroid- 18-acidlactone obtained, after introduction of a 4:5- double bond andketalization of 0x0 groups in 3- and 20- positions, the 0x0 group formedis reduced to the 11,8- hydroxy-group by the aid of a complex lightmetal hydride and, in the compound thus obtained, the 20-hydroxy groupis dehydrogenated to the 20-0xo group with a member selected from thegroup consisting of (1) a compound of hexavalent chromium and (2) analuminum alcoholate in the presence of a ketone.

12. Process as claimed in claim 10, wherein in a steroid- 18-aldehydeobtained, after introducing of a 4:5-double bond, and ketalization of0x0 groups in 3-, 18- and 20- positions, the ll-oxo group formed isreduced to the 1118- hydroxy-group by the aid of a complex light metalhydride.

13. Process as claimed in claim 10, wherein there is used chromiumtrioxide in the presence of an acid.

14. Process as claimed in claim 10, wherein there is used chromiumtrioxide in pyridine.

15. Process as claimed in claim 10, wherein there is used sodium boronhydride as the complex light metal hydride in alkaline solution.

References Cited by the Examiner Cainelli et al.: Helv. Chim. Acta, vol.42, No. 3 (1959), pages 1124-1127.

Heusler et al.: Experiential, vol. 16, No. 1 (Jan. 15, 1960), pages21-24.

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, Examiner.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THEFORMULA